Therapeutic antibodies are increasingly being used for the treatment of various disorders, such as immunological disorders, inflammatory disorders, cancers or infectious diseases. These therapeutic antibodies are typically monoclonal antibodies, derived from various species, or chimeric or humanized antibodies (see e.g., Levene et al., 2005, J. Royal Soc. Med. 98, pp 145-152). Depending on the disease, therapeutic antibodies directed against the following distinct target antigens have been used: TNFα, VEGF, HER2, CD20, IGF-I receptor, EGFR, or the IL-6 receptor, for instance.
Anti-TNFα therapeutic antibodies are widely used to treat patients with various inflammatory or autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, Crohn's disease or ankylosing spondylitis. Examples of such anti-TNFα agents include Etanercept, Golimumab, Certolizumab pegol, Adalimumab, or Infliximab. Etanercept is a dimeric fusion protein consisting of two extracellular domains of the human p75 TNFα receptor, linked to the Fc fragment of a type 1 human immunoglobulin (IgG1). Golimumab is a human anti-TNFα monoclonal antibody. Certolizumab pegol is a monoclonal antibody, more precisely a PEGylated Fab′ fragment of a humanized anti-TNFα monoclonal antibody. Adalimumab is a humanized anti-TNFα monoclonal antibody and Infliximab is a chimeric anti-TNFα monoclonal antibody (Perdriger A, Infliximab in the treatment of rheumatoid arthritis. Biologics: Targets & Therapy 2009:3 183-191). These antibodies bind TNFα and block its inflammatory action.
Further examples of therapeutic antibodies include, without limitation, an anti-IL-6R monoclonal antibody as disclosed in WO2004/096274 and an anti-IGF-IR antibody as disclosed for instance in WO2005/005635.
During treatment with therapeutic antibodies, however, an immune response against the therapeutic antibody itself can be raised, and patients often develop, over the course of the treatment, antibodies against the drug itself (“Anti-Drug Antibodies”). As a result, the plasmatic rate of therapeutic antibody decreases and simultaneously or subsequently, the disease symptoms reappear or increase. These Anti-Drug Antibodies (“ADA”) therefore reduce or totally neutralize the effect of a therapeutic antibody (see e.g., Wolbink G J, et al. Development of anti-Infliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis & Rheumatism, 2006 54(3): 711-715; G. M. Bartelds, et al. High levels of human antibodies to adalimumab in a patient not responding to adalimumab treatment. Anna Rheum Dis 2006; 65:1249-1250). The detection of these ADA in samples from a subject therefore may represent a method of monitoring patients over the course of the treatment.
Methods for detecting ADA have been reported in the art, such as for instance in WO2008/137885, WO2007/101661, or WO2009/091240. The methods referred to in these applications are immunological methods using capture and label antibodies. Further methods and recommendations regarding ADA detection have been reported in Anthony R. Mire-Sluis, et al., Journal of Immunological Methods, 333 (2008) 1-9; Eugen Koren, et al., Journal of Immunological Methods, 289 (2004) 1-16. Wolbink et al (Arthritis & Rheumatism 54 (2006) 711-715) also discusses the clinical relevance of anti-infliximab antibodies in patients with rheumatoid arthritis. None of these methods propose to simultaneously evaluate ADA and the relevant antigen. None of these methods recognize the relevance of a combined detection of various parameters.
Patton et al (J. Immunol. Methods 304 (2005) 189-195) relates to an ELISA method for detecting antibodies against proteins.
The present invention relates to improved methods of detecting ADA and monitoring patients undergoing therapeutic antibody treatments.